Synthetic nanopores enable fundamental and applied studies of individual biomolecules in high throughput; their performance is, however, subject to some limitations.
For example, recordings of resistive current pulses during the translocation of molecules through electrolyte-filled nanopores make it possible to study the size (1-6), conformation (7-8), and activity of single molecules in situ (11-17). This technique can characterize hundreds of unlabeled single molecules per second in physiological solutions and yields distributions of measured parameters from these single-molecule investigations (16,18). Nanopore-based experiments are relatively simple to set up, execute, and analyze, while providing unique information content including sub-molecular detail on the composition of individual molecules (18) and on the formation of molecular complexes or aggregates (2,19). In addition, nanopores hold tremendous promise for applied fields such as single-molecule binding assays (2,16,20), portable detection of (bio)warfare agents (4,5,21), and ultra-fast sequencing of DNA or RNA (22,23). In order to accelerate the realization of this potential, several challenges should be addressed; these include:                Difficulty to fabricate synthetic nanopores reliably on the (sub-) nanometer scale (24).        Difficulty to adjust or actuate the pore diameter, in situ (25,26).        Limited control of translocation times of single-molecule analytes, often leading to incomplete time resolution of translocation signals and associated inaccurate determination of the amplitude and duration of resistive pulses (27-29).        Limited control of the surface chemistry inside synthetic pores (16).        Non-specific interactions of analytes with the pore walls (2,6,30).        Pore clogging (16).        Low frequency of translocation events at low analyte concentrations (31); and        Poor specificity for analytes (16).        
In conventional Coulter counting there are two liquid compartments with an electrode in each compartment and a pore connecting the compartments. The electrodes measure current or other electrical parameters, such as voltage, resistance, and capacitance, between the two compartments. When a particle from one of the liquid compartments enters the pore, it perturbs the electric field. The so-called Coulter effect is well-known and provides that the field is perturbed by a passage of a particle through the pore, and the effect is detectable and measurable especially when the pore and the particle are of comparable dimension. As the pore diameter decreases, smaller objects can be detected using the Coulter principle.
For detection, there must be a measurable change in an electrical parameter for each particle that passes through the pore. It has been theoretically and empirically found that the length of the pore is important, with the result that for small particles like a protein the pore must be very short in order to achieve enough perturbation in the electrical signal for it to be measured. So, for measuring nano-sized particles such as a protein, not only is a small diameter pore required but also a very short pore. Coulter counting of nano-sized particles has been limited by the fact that when a protein or other bio-molecule goes through or translocates through a short pore, the transit time is so short that the best available electronics cannot resolve the translocation.
A way of overcoming these and other drawbacks of using the Coulter principle on nano-sized analytes would be an advance.